Phenethylamine derivatives



United States Patent 3,292,674 PHENETHYLAMINE DERIVATIVES Andre L.Langis, St. Laurent, Quebec, and Marie- Geuevieve Paula Stegen,Montreal, Quebec, Canada, assignors to American Home ProductsCorporation, New York, N.Y., a corporation of Delaware No Drawing. FiledMay 24, 1961, Ser. No. 112,197

Claims priority, application Canada, Mar. 5, 1960, 793,835; Mar. 3,1961, 818,303 1 Claim. (Cl. 260--309.6)

This application is a continuation-impart of our copending applicationSerial No. 92,123, filed February 28, 1961, now abandoned.

This invention relates to phenethylamine derivatives and theirpreparation.

More particularly, it relates to phenethylamine derivatives of thegeneral formula in which R is selected from the group consisting ofalkyl, aryl, aralkyl, hydroxy substituted aralkyl, alkoxy substitutedaralkyl, alkyl substituted aralkyl, phenoxy methyl, alkoxy substitutedphenoxy methyl, alkoxy benzyl, cycloalkenyl and pyridyl. R is aralkyl, Ris selected from the group consisting of alkyl and aryl, and R isselected from the group consisting of hydrogen and lower alkyl.

Also included in the invention are the pharmacologically acceptablesalts, intermediates and methods of preparation.

The phenethylamine derivatives of the invention are pharmacologicallyactive, being especially useful as bronchodilators and antihistaminicagents for humans or animals. As such, they are equivalent to theirpharmacologically water-soluble acceptable salts which may beadministered orally or by subcutaneous injection or in aerosol form.Other compounds of the invention are useful as intermediates in thepreparation of the pharmacologically active compounds.

When administered orally, subcutaneously, or as an aerosol, theantihistaminic activity of the active compounds may be demonstrated invivo by the guinea pig aerosol test, described by O. H. Siegmund, J.Pharmacol. Exp. Therap, vol. 90, p. 254 (1947) and in vitro by theequally Well-known test of Magnus on the isolated guinea pig ileum. Thebronchodilator activity may be shown in the cat, using the test methodofKonZett described in Arch. fiir Exper. Pathol. PharmakoL, vol. 195, p.71 (1940) and by the guinea pig aerosol test mentioned above.

Further advantages of the active compounds are that they do not act likethe sympathomimetic amines and their salts, as may readily bedemonstrated in tests on the spontaneous activity of the isolated ratuterus or the guinea pig ileum. Neither do they cause the damage to theheart characteristic of the catecholamines, no significant effects onheart rate or blood pressure being demonstrable in the dog, nor anyevidence of tachycardia.

Other advantages of the above compounds and of their water-soluble,pha-rmacolog-ically acceptable salts are that they cause neitherstimulation nor depression, and that they possess bronchodilatoractivity of long duration after oral administration.

The compounds of the by the following process.

invention may be produced 3,202,674 Patented An 24, 1965 R2 R1NH( J-ONin in which R R and R are as defined above.

The latter nitrile is reduced preferably with lithium aluminum hydrideto obtain a substituted diamine of the formula in which R R and R are asdefined above. The latter compound is reacted Withan acid or itscorresponding lower alkyl ester of the general formula RCOOH orRCOOAlkyl in which R is as defined above.

If the reaction mixture is heated at 230 C. to 250 C. for thirty minutesand not subjected to distillation, there is obtained a mixture of asubstituted acetamide of the general formula in which R, R R and R areas defined above, and a corresponding substituted im-idazoline of thegeneral formula mentioned above. The above mixture may be converted to amixture of the corresponding hydrohalides, preferably thehydrochlorides, by conventional means, and the active imidazoline as anon-toxic salt may then be derived in several different Ways as follows.

For example, the mixture of hydrohalides may be separated byfractionated crystallization to remove the substituted acetamide andthen treated with a Weak base to obtain the substituted imidazoline as abase. The latter may be in turn converted to a non-toxic salt.

Alternatively, the mixture of the substituted diamine of the aboveformula with an acid or its lower alkyl ester of the formula mentionedabove may be heated, preferably for from one to two hours, at atemperature of from 230 C. to 250 C., whereupon the substitutedacetamide of the formula mentioned above is substantially converted intothe correspondingly substituted imidazoline so that almost the entireyield is of the latter.

In an alternative procedure, the substituted acetamide of the formulamentioned above may be isolated and heated at 230 C. to 250 C. toconvert it to the correspondingly substituted imidazoline.

In a still further procedure the step of condensing the substituteddiamine of the formula mentioned above with an acid or its correspondinglower alkyl ester of the formula mentioned above may be carried out asfollows. The substituted diamine is heated, preferably at a temperatureof from 230 C. to 259 C. for from one-half 83 hour to two hours,followed by distillation, thereby to convert the resulting reactionproduct completely to a correspondingly substituted imidazoline of thegeneral formula mentioned above.

The invention also includes as new products the intermediates describedherein and the dihydrohalides thereof, preferably the hydrochlorides.

For use as pharmacologically active substances the imidazolines of thisinvention, in the form of pharmacologically acceptable salts, preferablythe hydrochlorides, may be compounded in a known manner to form novelcompositions. For example, they can be put up with pharmaceuticallyacceptable carriers. Such carriers are commonly made up of starch,lactose, aluminum and magnesium stearates and possibly other functionalagents. The mixture may be prepared and granulated, ground and pressedinto tablets in the usual manner. For subcutaneous or aerosol use, thematerial may be put up in a sterile aqueous isotonic solution.

A number of the compounds of this invention possess an asymmetric carbonatom and may be resolved into their optically active enantiometers. Oneof the compounds of this invention corresponding to the generic formulamentioned above in which R is benzyl, R is phenethyl, R is methyl and Ris hydrogen, has been smoothly dehydrogenated, introducing a double bondbetween carbon atoms 4 and 5 to give the corresponding imidazole of thefollowing formula ornament,

NCCH3 o rnomo N-CH The following examples describe preferred procedureswhich further illustrate the invention.

EXAMPLE 1 Alpha (Z-phenethylamirzo) propionitrile III 104.06 g. (1 mole)of sodium bisulfite are dissolved in 500 cc. of water. The solution iscooled to C. and 44.05 g. (1 mole) of acetaldehyde is added dropwisemaintaining the temperature of the reaction mixture at -l6 C. 121 g.(1.0 mole) of beta-phenethylamine are then added dropwise to the sodiumbisulfite addition product. A solution of 65.12 g. (1.0 mole) ofpotassium cyanide in 250 ml. of water is then added to the solutionwhich is kept at a temperature of 1516 C. throughout the addition.

The reaction mixture is then allowed to stir at room temperature for aperiod of two hours. A thick oil forms on the surface and is extractedwith benzene. The

benzene extract is washed with water, dried over sodium sulfate and thebenzene evaporated under reduced pressure. The yellow oil so obtained isdistilled under vacuum. Yield: 112 g. B.P. 133 C. at 14mm.

EXAMPLE 2 2-(beta-pltcnezhylamiuo) propylamiize dihydrochloride IV 100g. of alpha-(2-phenethylamino) propionitrile dissolved in 100 cc. of dryether are added dropwise to a mixture of 23.0 g. of lithium aluminumhydride in 250 ml. of ether. The mixture is heated to reflux for aperiod of one hour. 53 ml. of water are then added dropwise to themixture which has been previously cooled in an ice and water bath. Theinorganic salts are filtered oil, the ether evaporated under reducedpressure and the residue distilled under vacuum. Yield: 62 g., B.P. 138-140 C., at 8 mm. A 5g. sample of this material is dissolved in 50 ml. ofether and the solution poured in cold ethereal hydrogen chloride. Thecrystals are filtered off and recrystallized from a methanol andisopropanol mixture. Yield: 4.5 g., M.P. 222-223 C.

Calculated for C H N Cl z N, 11.15%; Cl, 28.2%. Found: N, 11.02%; Cl,28.34%.

EXAMPLE 3 1-betaphcnctlzyl-2-beuzyl-5-methyl imidazoline hydrochlorideIV 17.8 g. of 2-(beta-phenethylamino) propylamine and 16.4 g. of ethylphenylacetate are heated at 240245 C. for a period of one hour and theethanol is distilled off as it forms. The reaction mixture is cooled andthe thick oily residue is distilled under high vacuum. Yield: 10.0 g.,B.P. 166l68 C., at 0.18 mm. The product is dissolved in 250 ml. of dryether and poured in cold ethereal hydrogen chloride. The precipitate isfiltered oif and recrystallized from acetone and methanol mixture.Yield: 7.8 g., M.P. 198-200" C.

Calculated for C H N QHCI: C, 68.8%; H, 7.58%; phenylacetamide as acolorless oily residue.

EXAMPLE 4 N-bcta-(Zphenethylamino)propyl p/zenylacatamide hydrochlorideV aud 1-(bela-phenethyl)-2-benzyl-5-inethyl imidazoline VI A mixture of2-(beta-phenethylamine) propylamine IV (387 g.) and ethyl phenylacetate(356 g.) is warmed at 245 C. for a period of 30 minutes. When all theethanol has distilled over, the oily residue is cooled and compounds Vand VI are separated by conversion to the hydrochloride.

(a) Isolation of l-(beta-phelzethyl)-2-beuzyl-5-methyl imidazolinehydrochloride VI.--The liquid residue obtained above (54-6 g.) isdissolved in 1 litre of acetone and treated with 3.5 litres of asaturated ethereal hydrogen chloride solution. The mixture ofcrystalline hydrochlorides which separates is collected andrecrystallized three times from a methanol acetone mixture to give 146g. of compound VI. The more soluble compound V remains in solution andis isolated as described below:

Compound VI M.P. 197-198" C.-Calculated for C H N HCI: C, 72.3%; H,7.37%; N, 8.90%; Cl, 11.28%. Found: C, 72.0%; H, 7.19%; N, 8.68%; Cl,11.27%.

(b) Free base of Vl.A solution of 157 g. of compound VI hydrochloride in2 litres of water is treated with 60 g. of sodium carbonate andextracted with benzene. Distillation of the benzene extract under thehigh vacuum gives g. of a colorless liquid, B.P. C. at 0.2 mm.

Calculated for C H N C, 81.9%; H, 7.98%; N, 10.07%. Found: C, 80.9%; H,7.95%; N, 10.18%.

(c) Isolation of N-(beta-Z-phenethylamiizo)-pr0pyl phenylacctamide HClV.-The methanol acetone which remains after removal of compound V isconcentrated under vacuum to remove the solvent and the residue soobtained after two recrystallizations from water gives 70.0 g. ofcompound V, M.P. 143-145 C.

Calculated for C H N QHCl: C, 68.8%; H, 7.58%; N, 8.43%; Cl, 10.6%.Found: C, 68.4%; H, 7.52%; N, 8.47%; Cl, 10.6%.

((1) Free base 0 compound V.Two grams of the above hydrochloride aretreated with 50 ml. 14% aqueous ammonia solution, extracted with ether,and the solvent evaporated, yielding N-beta-(Z-phenethylamino)-propylphenylacetamide as a colorless oily residue.

EXAMPLE 5 Conversion of compound V to compound VI EXAMPLE 6 1-beta-phenezhyl) -2-benzyl-5-methyl-imidazotine hydrobromide Whendissolving 2 g. of the residue obtained as above after heating compoundV in 25 ml. of ether and treating with 5 ml. 48% hydrobromic acid thecolorless crystalline N- beta-phenethyl -2-benzyl-S-methyl-imidazolinehydrobrornide is obtained a sample of which, after recrystallizationfrom methanol melts at 216217 C.

EXAMPLE 7 1- beta-phenethyl) -2-benzyl-5-1nethyl-imidazoline The racemicform of that compound has been prepared according to the methoddescribed in our copending patent application, Serial No. 92,123. It wasseparated into its two optical isomers, the laevo form (1a) and thedextro form (112) as follows:

a) Laev0-1 beta-phenethyl) -2-benzyZ-S-methylimidaz0lz'ne.-31.4 grams(0.10 mole) of the racemic form of 14beta-phenethyl) 2-benzyl-5-methylimidazoline hydroohloride were dissolved in water and converted to thecorresponding free base by the addition of 4.0 grams of sodiumhydroxide. The free base was extracted with ether and the ether extractdried over sodium sulfate.

11.6 grams (0.05 mole) of dextro-10-camphorsulfonic acid dissolved in 50ml. of methanol were added to the ether solution obtained above. Thedextro lc-amphorsulfonate was then precipitated by the addition of moreether. The product was recrystallized from isoprop-anol. 19.5 grams ofpure dextro-lO-camphorsultonic acid salt were obtained in this manner.

The camphorsulfonic acid salt was then treated with dilute sodiumhydroxide solution and the free base was extracted with ether. The freebase was converted to the corresponding hydrochloric acid salt byconventional method. 11.9 grams oflaevo-l-(beta-phenethyl)-24benzyl-S-rnethylimidazoline hydrochloride,having a rotation of [aJ -94", were obtained in this manner.

(b) Dextro-1( beta-phenethyl) -2-benzyl-5-methylimidtazolina-To themother liquor obtained after the precipitation ot the abovedextro-camphorsulfonate salt was added another 0.05 mole ofdextro-10-carnphorsultonic acid and the rotating isomer was precipitatedin the same manner as the rotating one. After several recrystallizationsfrom isopropanol pure dextro-camphorsulfonate salt was obtained. It wasconverted to the corresponding hydrochloric acid salt and 3.0 grams ofdextro-l-(beta-phenethyl)-2 benzyl-S-rnethylimidazoline hydrochlorideR-9578 having the following rotation [a] +94 were obtained.

EXAMPLE 8 1 beta-phenethyl) -2-phenyl-5-methylimidazoline By followingthe method described in Example 3 of our copending patent applicationabove-identified, but using 35.6 grams (0.2 mole) of 2-(betaphenethylamino) propylamine and 30.0 grams (0.2 mole) ethyl benzoate,heating at 230 C. for two hours, distilling off ethanol and water asthey were formed, cooling the reaction mixture and distilling it underhigh vacuum, there were obtained 23.0 grams of the title compound B.P.170172 C. at 0.28 mm. Hg. The compound was identified by analysis of the.picrate salt, M.P. 148-149 C.

Calculated for C H N NO C H OH: C, 58.42%; H, 4.70%; N, 14.19%. Found:C, 59.13%; H, 4.32%; N, 14.36%.

EXAMPLE 9 l-(beta-phenezhyl) -2-(beta-p henefhyl) -5-methylimidazolineFollowing the method described in Example 8, but using 35.6 grams (0.2mole) of 2-'(:beta-phenethylami-no) propylamine and 36.0 grams (0.2mole) of ethyl hydrocinnamate, heating at 260 C. for two hours and Work-6 ing up as above, there were obtained 26.3 grams of the title compound,B.P. ISO-152 C. at 0.04 mm. Hg, identified as the picrate salt, M.P.122-124 C. Calculated fGT C20H24N2'(NO2)3C6H2O4: C, H, 5.22%. Found: C,59.91%; H, 5.08%.

EXAMPLE 10 I beta-p'henethyl) -2-(3-pyridyl) -5-methy limidazolineFollowing the method described in Example 8, but using 356 grams (0.2mole) of 2-(betaepbenethyl-amino) propylamine and 30.2 grams (0.2 mole)of ethyl nicotin- =ate, heating at 260 C. for two hours, and working upas above, there were obtained 30.5 grams of the title compound, B.P.176-178 C. at 0.05 mm. Hg identified as the picnate salt, M.P. -151 C.

Calculated for C1I7H1QN3"(NO2)3C5H2OHI C, H, 4.48%; N, 17.00%. Found: C,56.16%; H, 4.31%; N, 17.00%.

EXAMPLE 11 1 beta-phenethyl) -2-( o-hyaroxyphenylmethyl)-5-mezhylimz'dazoline hydrochloride EXAMPLE 12 1-(beta-phenethyl)-2-p-hydr0xyphenylmethyI-S-methylimidazoline hydrochloride Following themethod described in Example 8, but using 10.0 grams of 2(beta-phenethylamino) propylamine and 10.0 grams ethyl .p-hydroxyphenylethylacetate heating at 220 C. for two hours, distilling 01f water andethanol as they were formed, cooling the reaction mixtu-re, dissolvingit in ether, pouring it in cold ethereal hydrocanbon chloride, andrecrystallizing from a mixture of isopropanol and ethanol, there wereobtained 9.0 grams of the title compound, M.P. 234235 C.

Calculated for C l-l N O-HOlz N, 8.46%; C l,

10.71%. Found: N, 8.31%; Cl, 10.56%.

EXAMPLE 13 1- (heta-pherzethyl) -2- (3,4-dihydr0xybenzyl)-5-methylimidazoline Following the method described in Example 8, butusing 9.2 grams of 2-(beta-phenethylamineo) propylamine and 10.0 gramsof 3,4-dimethoxypl1enylacetic acid, heating at 250 C. for thirty minutesand working up as described in Example 8, there were obtained 15.1 gramsof 1- (beta-phenethy-l) -2-'( 3',4'-dihydroxybenzyl -5-methyvlimidazoline, B.P. ISO-182 C. at 0.3 mm. Hg. The methoxy groupsin thatcompound were removed by hydrolysis by dissolving 4.53 grams of thecompound in 25 ml. of 48% hydrobromic acid, heating at reflux for eighthours, cooling, and recrystallizing from isopropanol, obtaining 2.4grams of the hydrobromide salt of the title com-pound, M.P. 225226 C.

Calculated for C H 'N O -HBr: N, 7.16%; Br.,

20.42%. Found: N, 6.92%; Br. 20.36%.

EXAMPLE 14 J-(beza-phenethyl)-2-(3'-meth0xybenzyl)5- methylimz'dazolinepropylamine and 25.0 grams (0.15 mole) of m-methoxyphenylacetic acid,heating at 250 C., for one hour and working up as described in Example8, there were obtained 35.3 grams of the title compound, B.P. 208211 C.at 0.07 mm. Hg, identified as the picrate salt, M.P. 129-130 C.

Calculated for C2OIIQ4NZO. 3C5I'IzOIIZ 13.03%. Found: N, 13.08%.

EXAMPLE .I-(bem-plzenethyl) -2-(4-mcflzylbenzyl) -5- meihylimidazolineFollowing the method of Example 8, but using 28.5 grams (0.16 mole) of2-(beta-phenethylamino) propylamine and 25.0 grams (0.16 mole) ofp-tolylacetic acid, heating at 260 C. for one hour, and working up asabove, there were obtained 30.0 grams of the title compound, B.P.192-196" C. at 0.1 mm. Hg, identified as the picrate salt, M.P. 129-130C.

Calculated for C2OH24N2.(NOZ)3CGH2OHI N, Found: N, 13.43%.

EXAMPLE 16 .1 -(beta-phenethyl -2- (2',4',64rimethylbenzyl -5-methylimidazoline EXAMPLE 17 l-(beta-phen ethyl)-2-phen0xymethyl-5-methylimidazolinc Following the method of Example 8, but using 35.6grams of 2-(beta-phenethylamino) propylamine and 30.4

grams of phenoxyacetic acid, heating at 245-255 C.

for 45 minutes and working up as above, there were obtained 37.0 gramsof the title compound, B.P. 180- 184 C. at 0.15 mm. Hg, identified asthe hydrochloride salt, M.P. 146149 C.

Calculated for C H N Ol-ICl: N, 10.72%. Found: N, 8.28%; Cl, 10.64%.

EXAMPLE 18 I-(beta-phenetlzyl) -2-(4'-meth0xyphen0xymethyl) -5-methylimidazoline Following the method of Example 8, but using 17.8grams of Z-(beta-phenethylamino) propylamine and 18.2 grams ofp-methoxyphenoxyacetic acid, heating at 230- 250 C. for thirty minutes,and working up as above, there were obtained 21.8 grams of the titlecompound, B.P. 180-190" C. at 0.15 mm. Hg, identified as the picratesalt, M.P. 130-132 C.

Calculated for CzgH24N202-2,4,6(NO2)3C H2OH: C, 56.43%; H, 4.92%; N,12.64%. Found: C, 56.93%; H, 4.54%; N, 12.39%.

EXAMPLE 19 l-(beta-phelzethyl) -2-(D,L-meth0xybenzyl -5-methylimidazoline Following the method of Example 8, but using 17.8grams of Z-(beta-phencthylamino) propylamine and 16.62 grams ofDL-methoxyphenylacetic acid, heating at 230 C. for thirty minutes, andworking up as above, there were obtained 20.6 grams of the titlecompound, B.P. 167-170 C. at 0.35 mm. Hg, identified as the picratesalt, M.P. 132-134 C.

Calculated for CH24N2O.2,4,6(NO2)3C6II2OH: C, 58.11%; H, 5.06%; N,13.02%. Found: C, 58.2%; H, 5.06%; N, 13.02%.

8 EXAMPLE 2 0 l-(beta-phenethyl) -.2-ethyl-5-methylimidazoline Followingthe method of Example 8, but using 17.8 grams of Z-(beta-phenethylamino)propylamine and 7.4 grams of propionic acid, heating at 230 C. forthirty minutes, and Working up as above, there were obtained 12.6 gramsof the title compound, B.P. 150-153 C. at 0.35 mm. Hg, identified as thepicrate salt, M.P. 144- C.

Calculated for C14II20N2.2,4,6 3C6H20H: N, 15.72%. Found: N, 15.55%.

EXAMPLE 21 1 -(beta-ph methyl) -2-(n-hcxyl) -5-methylimidazolineFollowing the method of Example 8, but using 35.6 grams ofZ-(beta-phenethylamino) propylamine and 26.03 grams of n-heptanoic acid,heating at 225235 C. for two hours, and working up as above, there wereobtained 35.0 grams of the title picrate salt, M.P. 8789 C.

Calculated for C ,-,H N .2,4,6(NO C H OH: N,

13.97%. Found: N, 14.01%.

EXAMPLE 22 1 (beta-phenetlzyl)-2-(a -cyclopentenylmethyl)-5-methylimidazoline Following the method of Example 8, but using 35.6grams of Z-(beta-phenethylamino) propylamine and 25.0 grams of a-cyclopentenylacetic acid, heating at 235 C. for thirty minutes, andworking up as above, there were obtained 36.5 grams of the titlecompound, B.P. 159-161 C. at 0.18 mm. Hg, identified as the picratesalt, M.P. 113114 C.

Calculated for C H N .2,4,6(NO C H OH: N,

14.08%. Found: N, 14.09%.

EXAMPLE 23 1 beta-phenethyl -2-naphthylmethyl-5-m ethylimidazolineFollowing the method of Example 8, but using 23.2 grams ofZ-(beta-phenethylamino) propylamine and 25.0 grams of l-naphthylaceticacid, heating at 250 C. for thirty minutes, and working up as above,there were obtained 33.3 grams of the title compound, B.P. 220-222 C. at0.28 mm. Hg, identified as the picrate salt, M.P. 172173 C.

Calculated for C23H24N2-2,4,6(NO2)3C6H2OH: N, 12.56%. Found: N, 12.66%.

EXAMPLE 24 (a) Alpha-(3-phenylpropylamino) pr0pi0nitrile.18.5 grams(0.14 mole) of 3-phenylpropylamine were added portionwise to 10.0 grams(0.14 mole) of lactonitrile. The reaction mixture was cooled with an iceand water mixture in between each addition. The mixture was leftstanding at room temperature for twenty hours. cc. of ether were addedandthe two layers were separated. The ether layer was washed with Water,dried over sodium sulfate and evaporated under reduced pressure. Theoily residue was distilled under vacuum. Yield: 25.5 grams, B.P. 134-136C. at 18 mm. A sample of the hydrochloric acid salt of this material wasprepared for analytical purposes, M.P. 146-148 C.

Calculated for C H N l-ICl: C, 64.13%; H, 7.62%. Found: C, 64.12%; H,7.75%.

(b) 2 (3 phenylpropylamino) propylamine-12.16 grams (0.32 mole) oflithium aluminum hydride were suspended in 250 ml. of dry ether. 42.7grams (0.32 mole) of anhydrous aluminum chloride dissolved in 300 ml. ofdry ether were added rapidly through a dropping tunnel to the reactionmixture. After stirring for five minutes, 60 grams (0.32 mole) ofalpha-(3-phenylpropylamino) propionitrile dissolved in 250 ml. of dryother were added dropwise maintaining the temperature of the reactionmixture below the boiling point of ether. The mixture was stirred atroom temperature for one hour after which 50 ml. of water followed by455 ml. of 6 N hydrosulturic acid were added dropwise. 325 ml. of waterwere added to the mixture, the two layers were separated and the aqueousfraction was extracted with ether. The aqueous layer was then broughtback to pH 11 with potassium hydroxide and the diamine was extractedwith ether. The ether extract was dried over sodium sulfate andevaporated to dryness under reduced pressure. Yield: 35.2 grams. Bl.160-l72 C. at 24 mm. A sample of the hydrochloride of this material wasprepared for analytical purposes, M.P. 199201 C.

Calculated for C H N .2HCl: N, 26.74%. Found: N, 27.74%.

(c) 1-(3-phenylpr0pyl)-2 =benzyl methylim idaZoline-Following the methodof Example 8, but using 35.2 grams (0.18 mole)of 2-(3-phenylpropylamino)propylamine and 29.5 grams (0.18 mole) of ethyl phenylacetate, heatingat 270 C. for two hours, and working up as above, there were obtained33.9 grams of the title compound, B.P. l78-186 C. at 0.02 mm. Hg,identified as the picrate salt, M.P. 124-l26 C.

Calculated for C H N .(NO C H OH: N, 13.43%. Found: N, 13.99%.

EXAMPLE 25 (a) Alpha-(1 methyl 2 phenethylam-ino) pr0pionitrite-190.0grams (1.41 mole) of amphetamine were added portionwise to 101.1 grams(1.41 mole) of lactonitrile cooling the solution between each addition.The reactants were left standing at room temperature for two hours andthen they were heated on a steam bath for one hour. 250 cc. of etherwere added to the mixture and the water layer was separated oif. Theether fraction was dried over sodium sulfate and the solvent evaporatedunder reduced pressure. The residue was distilled under vacuum. Yield:166.6 grams, B.P. 1l4117 C. at 23 mm.

(b) 2 (alpha methyl-beta-phenethylamino) propylamine-466.0 grams ofalpha (l-methyl 2 phenethylamino) propionit-rile were added dropwise toa suspension of 35.0 grams of lithium aluminum hydride in 500 grams ofether maintaining the temperature of the reactants below 10 C. Stirringat 10 C. was continued for an additional two hours. 77.0 ml. of waterwere added dropwise, the inorganic salts were filtered off and thesolvent was evaporated under reduced pressure. Yield: 44.8 grams, B.P.l45-l47 Cat mm. A sample of the hydrochloric acid salt of this materialwas prepared for analytical purposes, M.P. 254-256 C.

Calculated for C H N lHClz N, 11.34%; Cl, 28.69%. Found: N, 10.88%; Cl,27.28%.

(c) 1-(alpha-methyl-bem-phenethyl) -2-benzyl-5methylimidazoiine.-Following the method of Example 8, but using 37.6grams (0.2 mole) of Z-(aIpha-methyl-betaphenethylamino) propylamine and27.2 grams (0.2 mole) of phenylacetic acid, heating at 260 C. for thirtyminutes, and working up as above, there were obtained 24.5 grams of thetitle compound, B.P. 208-211 C. at 0.8

Hg, identified as the hydrochloride salt, M.P. 224- 226 C.

Calculated for C H N .HCl: N, 8.52%; Cl, 10.77%. Found: N, 8.15%; Cl,10.65%.

EXAMPLE 26 (a) 2-beta-phenethylaminobutyronitrile.-l04.1 grams (1.0mole) of sodium bisulfite were dissolved in 250 ml. of water. grams (1.0mole) of propionaldehyde were added dropwise maintaining the temperatureof the reaction mixture below 15 C. 121.0 grams (1.0 mole) ofbeta-phenethylamine were then added dropwise to the sodium bisulfiteaddition product. Finally a solution of 65.2 grams (1.0 mole) ofpotassium cyanide in 150ml. of water was added The solution was cooledto 10 C. and 58.1

dropwise to the solution which was kept at room temperature throughoutthe addition. The mixture was stirred at room temperature for one hour.'The oily layer was extracted with benzene, the benzene extract was thenwashed with water and dried over sodium sulfate. The benzene was thenevaporated under reduced pressure. Yield: 168 grams of crude material.We used the nitrile in the crude form for the next reaction becausethere was considerable decomposition when we tried to distill it.

(b) Z-beta-phenethylaminobutylamine.168.0 grams of crudeZ-beta-phenethylaminobutyronitrile were added dropwise to a mixture of3.80 grams (1.0 mode) of lithium aluminum hydride in 500 ml. of dryether keeping the temperature of the reaction mixture below 10 C. Themixture was then stirred at room temperature for thirty minutes. 40 ml.of water followed by 50 ml. of 20% sodium hydroxide solution and another25 ml. of water were added dropwise. The inorganic salts were filteredon a Buchner funnel and the ether evaporated under reduced pressure. Theresidue. was then distilled under vacuum. Yield: 94.8 grams, B.P.160-165 C. at 20 mm. A sample of the hydrochloric acid salt of thismaterial was prepared for analytical purposes, M.P. 206-208 C.

Calculated for C H N 2HCl: N, 10.57%. Found: N, 10.41%.

(c) 1-beta-phenethyl-2-benzyl-5-ethylimidaZ0line.Fo1- lowing the methodof Example 8, but using 94.8 grams (0.5 mole) of2-beta-phenethylaminobutylamine and 68.0 grams (0.5 mole) ofphenylacetic acid, heating at 250 C. for one hour, and Working up asabove, there were obtained 88.9 grams of the racemic form of the titlecompound, B.P. 170-176 C. at 0.04 mm. Hg, identified as thehydrochloride salt, M.P. 172174 C.

Calculated for C H N 2HCl: N, 8.52%; Cl, 10.78%. Found: N, 8.40%; Cl,10.82%.

(d) Laevo-l-bem-phenelhyl 2 benzyl 5 ethylimidaz0line.88.9 grams (0.30mole) of racemic l betaphenethyl 2 benzyl 5 ethylimidazoline as obtainedabove was dissolved in cc. of hot isopropanol. A solution of 35.6 grams(0.15 mole) of dextro-lO-camphorsulfuric acid dissolved in 50 ml. of hotisopropanol was added to the imidazoline solution. The mixture wascooled and the crystalline salt was filtered on a Buchner funnel anddried. Yield: 66.6 grams, M.P. 197205 C. The product was recrystallizedfrom isopropanol. Yield: 56.4 grams, M.P. 208-210 C. This material wasconverted to the free base by treatment with base and the hydrochloricacid salt prepared by the conventional method. Yield: 26.3 grams, M.P.169-171" C.,

EXAMPLE 27 (a) Alpha-(2 phenethylamino) valer0v1itrile.--52.03 grams(0.50 mole) of sodium bisulfite were dissolved in 250 ml. of water. 31.0grams (0.50 mole) of butyraldehyde were added dropwise maintaining thetemperature of the reaction mixture below 35 C. 60.5 grams (0.5 mole) ofbeta-phenethylamine were then added dropwise to the sodium bisulfiteaddition product. Finally a solution of 32.6 grams (0.50 mole) ofpotassium cyanide in ml. of water was added dropwise. The solution wasstirred at room temperature for two hours. The product was extractedwith benzene, the benzene extract was washed with water and dried oversodium sulfate. The solvent was evaporated under reduced pressure. Theresidue was distilled under vacuum. Yield: 26.7 grams. B.P. 138-148 C.at 20 mm.

(b) 2 (beta phenethylamino) valerylamine.-26.7 grams (0.13 mole) ofalpha (2-phenethylamino)-valeronitrile dissolved in 100 ml. of dry etherwere added dropwise to a mixture of 5.0 grams (0.13 mole) lithiumaluminum hydride in 500 ml. of ether maintaining the temperature of thereaction mixture below 10 C. The mixture was then stirred at roomtemperature for thirty minutes. 5 ml. of water followed by 10 ml. of 20%sodium hydroxide solution and another ml. of water were added dropwisemaintaining the temperature of the mixture below C. throughout theaddition. The inorganic salts were filtered off and the solventevaporated under reduced pressure. The residue was distilled undervacuum. Yield: 10.4 grams, B.P. 177182 C. at mm.

(c) I-(beta phenezhyl) 2 benzyl 5 propylimidaz0line.Following the methodof Example 8, but using 9.4 grams (0.046 mole) ofZ-(beta-phenethylamino) valerylamine and 6.3 grams (0.046 mole) ofphenylacetic acid, heating at 250 C. for sixty minutes and working up asabove, there were obtained 9.2 grams of the title compound, B.P. 169171C. at 0.03 mm. Hg, identified as the hydrochloride salt, M.P. 177179 C.

Calculated for C H N .HCl: Cl, 10.34%. Cl, 10.45%.

Found:

EXAMPLE 28 (a) 2-(beta-phenethylamino) 3-methylbutyronitrile. 104.1grams (1.0 mole) of sodium bisulfite were dissolved in 500 cc. of water.70.0 grams (1.0 mole) of isobutyraldehyde were added dropwisemaintaining the temperature of the reaction mixture at C. 121.0 grams(1.0 mole) of beta-phenethylamine were then added dropwise to the sodiumbisulfite addition product. Finally a solution of 65.2 grams (1.0 mole)of potassium cyanide in 250 cc. of water was added dropwise while thereaction mixture was kept at room temperature. The mixture was stirredfor two hours. The oily layer was extracted with benzene, the benzeneextract was dried over sodium sulfate and the solvent evaporated underreduced pressure. The residue was distilled under vacuum. Yield: 54.0grams, B.P. 145149 C. at mm. A sample of the hydrochloric acid salt ofthis material was prepared for analytical purposes, M.P. 143-145 C.

Calculated for C H N -HClz N, 11.73%. Found: N, 11.23%.

' (b) 2-(beta-p/zenethylamine) 3-methylbutylami1ze.- 52.1 grams (0.258mole) of 2-(beta-phenzthylamino)-3- methylbutyronitrile dissolved in m1.of dry ether were added dropwise to a mixture of 9.88 grams (0.26 mole)of lithium aluminum hydride in 500 ml. of ether maintaining the temerature of the reaction mixture below 10 C. The mixture was then stirredat room temperature for sixty minutes. The temperature of the reactantswas then lowered to 10 C. and 10 ml. of water followed by 20 ml. of a20% sodium hydroxide solution and finally by 5 ml. of water were added,dropwise. The inorganic salts were filtered off and the ether evaporatedunder reduced pressure. The residue was distilled under vacuum. Yield:13.0 grams, B.P. 168l72 C. at 17 mm. A sample of the hydrochloric acidsalt of this material was prepared for analytical purposes, M.P. 251255C.

Calculated for C H N -2HCl: N, 10.11%. Found: N, 9.85%.

(c) I-(beta-plzenethyl) 2 benzyl 5 isopropylimidazoline-Following themethod of Example 8, but using 12.0 grams (0.08 mole) ofZ-(beta-phenethylamino)-3- methylbutylamine and 10.9 grams (0.08 mole)of phenylacetic acid, heating at 265 C. for. thirty minutes, and workingup as above, there were obtained 15.4 grams of the title compound, B.P.190200 C. at 0.08 mm. Hg, identified as the hydrochloride salt, M.P.153-155" C.

Calculated for C H N -HCl: C, 73.57%; H, 7.94%; Cl, 10.34%. Found: C,73.81%; H, 7.98%; Cl, 10.48%.

EXAMPLE 29 (a) AIpha-(beta-pheizethylamino) phenylacetonitrile. 104.06grams 1.0 mole) of sodium bisulfite were dissolved in 2,000 ml. ofWater. 106.1 grams (1.0 mole) of benzaldehyde were added dropwisemaintaining the temperature of the reaction mixture below 30 C. 121.2grams (1.0 mole) of beta-phenethylamine were added dropwise alwaysmaintaining the temperature of the reaction mixture below 30 C. Asolution of 65.1 grams (1 mole) of potassium cyanide in 250' cc. ofwater was added dropwise. The reaction mixture was stirred at roomtemperature for one hour. The crystalline material was filtered on aBuchner funnel and dried in a vacuum oven. The product wasrecrystallized from methanol. Yield: 99.6 grams, M.P. 82-87 C.

(b) 2-(beta-phenethylamino) 2 plzerzethylaminc. 5 grams (0.13 mole) oflithium aluminum hydride were suspended in ml. of dry ether. 17.3 grams(0.13 mole) of aluminum chloride (anhydrous) dissolved in 200 ml. ofether were added rapidly through a dropping tunnel to the reactionmixture. After stirring for fifty minutes, 31 grams ofalpha-(beta-phenethylamino) phenylacetonitrile dissolved in 250 ml. ofdry ether were added dropwise keeping the temperatureof the reactionmixture just below the boiling point of ether. The mixture was stirredat room temperature for one hour, after which 20 ml. of water were addeddropwise. 182 ml. of 6 N hydrosulfuric acid were added dropwise followedby 130 ml. of water. The two layers were separated and the aqueous layerwas extracted with ether. The aqueous layer was then brought to pH 11with potassium hydroxide. The diamine was then extracted with ether, theether extract dried over sodium sulfate and evaporated under reducedpressure. The oily residue was distilled under vacuum. Yield: 22.6grams, B.P. 219223 C. at 19 mm. A sample of the hydrochloric acid saltof this material was prepared for analytical purposes, M.P. 247- 250 C.

Calculated for C H N -2HCl: C, 61.34%; H, 7.08%; CI, 22.64%. Found: C,61.19%; H, 7.12%; Cl, 22.75%.

(c) l-(beta-phenethyl) 2 benzyl 5 phenylimid- Molina-Following themethod described in Example 8, but using 19.0 grams (0.05 mole) ofZ-(beta-phenethylamino)-2-phenethylamine and 8.2 grams (0.05 mole) ofethylphenylacetate, heating at 240245 C. for two hours, and working upas above there were obtained 9.7 grams of the title compound, B.P.222-224 C. at 0.03 mm. Hg, identified as the picrate salt, M.P. 126128C.

Calculated torC H N (N0 C H OH: C, 63.26%; H, 4.78%; N, 12.30%. Found:C, 63.72%; H, 4.71%; N, 12.16%.

EXAMPLE 30 (a) Alplza,alpha-dimethyl-(Z-phenethylamino) acetonz'trile.166.5 grams of sodium bisulfite were dissolved in 500 ml. of Water. Thesolution 'was cooled to 10 C., and 45.24 grams of acetone were addeddropwise maintaining the temperature of the reaction mixture at 15- 16C. 94.5 grams of beta-phenethylamine were then added dropwise to thesodium bisulfite addition product. Finally a solution of 104 grams ofpotassium cyanide in cc. of water was added to the solution which waskept at room temperature throughout the addition. The mixture wasstirred at 22 C. for two hours. The thick oil was then extracted withbenzene 2x200 cc. The benzene extract was washed with water and thendried over sodium sulfate. The benzene was evaporated under reducedpressure and the residue distilled under vacuum. Yield 66 grams, B.P.126130 C. at 19 mm. A sample of the hydrochloric acid salt of thismaterial was prepared for analytical purposes, M.P. 124-126 C.

Calculated for C H N .HCl: N, 12.46%; Cl, 15.77%. Found: N, 12.40%; Cl,15.86%.

(b) 2 (beta phenetlzylamino) 2 methylpropylamine.73.3 grams ofalpha,alpha-dimethyl-(2-phenethylamino) acetonitrile dissolved in 150ml. of dry A.R. ether were added dropwise to a mixture of 15.2 grams oflithium aluminum hydride in 500 ml. of dry ether. The mixture wasstirred at room temperature for a period of thirty minutes. 30 ml. ofwater were added dropwise to the reaction mixture. The inorganic saltswere filtered off on a Buchner funnel and the ether evaporated underreduced pressure. The oily residue was distilled under vacuum. Yield:23.5 grams, B.P. 142-148" C. at 13 mm. A sample of the hydrochloric acidsalt of l3 this material was prepared for analytical purposes, M.P.257-259 C. I Calculated for C H N 2HCl: Cl, 26.74%; 10.57%. Found: Cl,27.17%; N, 10.53%.

(c) l-(beta-phenethy'l)-2-benzyl 5,5 dim lhylimidqzolina-Following themethod of Example 8, but using 20.0 grams ofZ-(beta-phenethylamino)-2-methylpropylamine and 16.4 grams ofethylphenylacetate, heating at 240-250 C. for one hour, and working upas above, there were obtained 19.8 grams of the title compound, B.P.

174-l76 C. at 0.18 mm. Hg, identified as a hydrochloride salt, M.P.229-232 C.

Calculated for C H N .HClZ N, 8.52%; Cl, l0.778%. Found: N. 8.09%; CI,11.32%.

EXAMPLE 31 (a) Alpha (2 ph nethylamz'no) acetm'trile.-104.l grams (1.0mole) of sodium bisulfite were dissolved in 500 ml. of water. Thesolution was cooled to C, and 81.0 grams (1.0 mole) of formaldehyde (37%solution in water) were added dropwise maintaining the temperature ofthe reaction mixture at -16" C. 121 grams (1.0 mole) ofbeta-phenethylamine were then added dropwise to the sodium bisulfiteaddition product. Finally a solution of 65.12 grams (1.0 mole) ofpotassium cyanide in 250 ml. of water was added dropwise to the solutionwhich was kept at a temperature of 15-16 C. throughout the addition. Thereaction mixture was then stirred at room temperature for two hours. Thethick oil which floated on the surface was extracted with ether. Theether extract was dried over sodium sulfate and the ether evaporatedunder reduced pressure. The oil was distilled under vacuum. Yield: 61.0grams, HP. 152- 154 C., at 7.0 mm. A sample of the hydrochloric acidsalt of this material was prepared for analytical purposes, M.P. 161-164C.

Calculated for C H N ficlz Cl, 18.03%. Cl, 17.68%.

(b) N-(2-phenethyl) ethylene dizzmine.48.0 grams ofalpha-(2phenethylamino) acetonitrile dissolved in 100 ml. of dry etherwere added dropwise to a mixture of 11.5 grams of lithium aluminumhydride in 500 ml. of dry ether. The mixture was stirred and heated toreflux for two hours; 26.5 ml. of water were then added dropwise to themixture which had been previously Found:

cooled in an ice and water bath. The inorganic salts acetate were heatedat 250-260 C. for one and one half hours and the ethanol was distilledoff as it was formed. The reaction mixture was cooled and the thick oilwas dissolved in 100 ml. of ether. The ether solution was poured intocold ethereal hydrogen chloride. The gummy precipitate was crystallizedfrom an acetone and methanol mixture. Yield: 7.0 grams, M.P. 184-186 C.

Calculated for C H N Ol-lcl: C, 67.8%; H, 7.26%; N, 8.78%; C1, 11.12%.Found, C, 67.35%; H, 7.24%; N, 8.83%; Cl, 11.62%.

((1) J-(beta-phenethyl) 2 benzylimidaz0lz'ne.-Following the method ofExample 8, but using 26.6 grams of N'-(2-phenethyl) ethylene diamine and27.2 grams of ethylphenylacetate, heating at 250-270 C. for 1.5 hours,and working up as described in Example 8, there were obtained 23.4 gramsof the title compound, B.P. 166- 176 C. at 0.1 mm. Hg, identified as thehydrochloride salt, M.P. 209-211 C.

Calculated for C H N HCl: C, 71.9%; H, 7.04%;

i4 01, 11.79%. Found: c, 72.11%; H, 7.01; 01, 11.77%. EXAMPLE 32 (a)Alpha benzylaminopropionitrile.107.2 grams (1.0 mole) of benzylaminewere added portionwise to 71.01 grams 1.0 mole) of lactonitrile, coolingthe reaction mixture between each addition. The mixture was then heatedon a steam cone for three hours, 300 ml. of benzene were added and thetwo layers were separated. The benzene portion waswashed with water,dried over sodium sulfate and the solvent evaporated under reducedpressure. The residue was distilled under vacuum. Yield: 111.0 grams,B.P. 131-137 C. at 18 mm. A sample of the hydrochloric acid salt of thismaterial was prepared for analytical purposes, M.P. -152 C.

Calculated for C H N HCI: Cl, 18.02%. Found: Cl, 19.56%.

(b) vZ-benzylaminopropylamina.62.0 grams (0.39 mole) ofalpha-benzylaminopropionitrile dissolved in 50 cc. of dry ether wereadded dropwise to a mixture of 15.2 grams (0.4 mole) of lithium aluminumhydride in 500 cc. of dry ether maintaining the temperature of thereactants below 10 C. The mixture was stirred at room temperature forthirty minutes. 10 m1. of water followed by 25 ml. of a 25% sodiumhydroxide solution and another 10 cc. of water were added dropwisemaintaining the temperature of the react-ants below 10 C. The inorganicsalts were filtered oil and the solvent evaporated under reducedpressure. The residue was distilled under vacuum. Yield: 28.9 grams,B.P. 130-131 C. at 13 mm. A sample of the hydrochloric acid salt of thismaterial was prepared for analytical purposes, M.P. 121-124 C.

Calculated for C H N lHCl: Cl, 29.89%. Found: Cl, 29.66%. t

(c) 1-benzyl-2-beza-phenethyl-S-methylimidazoline.- Following the methodof Example 8, but using 27.9 grams (0.17 mole) of2-benzylaminopropylamine and 25.5 grams (0.17 mole) of hydrocinnamicacid, heating at 250 C. for one hour, and working up as above, therewere obt-ained 35.5 grams of the title compound, B.P. -167 C. at 0.06mm. Hg, identified as the picrate salt, M.P. 123-124 C.

Calculated for c19H2 N .(NO2)3C5H2OHI C, H, 4.97%; N, 13.80%. Found: C,58.93%; H, 4.66%; N, 13.70%.

EXAMPLE 33 l-(beta-phenethyl)-2b-enzyl-5-methylimidazoline 40.0 grams of1-(beta-phenethyl)-2-benzyl-5-methylimidazoline, as obtained in Example3 were placed into a 100 ml.three-neck flask equipped with a stirrer anda condenser. Four B.D.H. 0.5 grams Raney Nickel pellets Were added tothe oil and the mixture was heated at 260 C, until no more hydrogen wasgiven off, approximately thirty minutes. The product was then distilledunder high vacuum, yielding 28.4 grams of the title compound, B.P.ZOO-212 C. at 0.32 mm. Hg, identified as the hydrochloride salt, M.P.261-262 C.

Calculated for C H N HCI: C, 72.95%; H, 6.77%; N, 8.96%. Found: C,72.76%; H, 6.50%; N, 8.84%.

We claim:

A phenethylarnine derivative selected from the group which consists of abase of the formula N--Ra R-U:

-GH3 in which R is selected from the group consisting of benzyl,monohydroxybenzyl, methylbenzyl and naphthylmethyl; R is p-phenethyl; Ris selected from the group consisting of hydrogen and alkyl of from oneto three carbon atoms; and R is selected from the group consisting ofhydrogen and methyl; and the hydrochloride and picrate salts thereof.

(References on following page) References Cited by the Examiner UNITEDSTATES PATENTS Wilson 260 -3096 McPhee 260570.5 lsler 260-3096Schlesinger et a1. 260578 Goodson 260'S70.5 Goldberg ct a1 260309.6Reynoldset a1. 2605 70,5 Carboni 260-4465 De Bcnneville 260465.5Thompson 260 309.6 Kroll et a1. 26,0'465.5 Ham et a1. 260 309.6 Matlinet a1. 260465 Weijlard 260465 1.6 2,915,431 12/59 Carron ct a1. 260309.62,937,203 5/60 Fuller 260-558 2,991,310 7/61 Phalen 2605'58 2,993,062 7/61 Noyle et a1 260-558 5 OTHER REFERENCES Gaylord: Reduction WithComplex Metal Hydrides, pages 731-41, N.Y., Interscience, 1956.

Kyrides et a1.: Jour. Org. Chem., vol. 12, pages 577-85 Schipper at211.: Eldqrfield Heterocycljc Compounds, vol. 5, pages 239-40 M, N.Y.',Wiley, 1957.

\VALTER A. MODANCE, Primary Exqminer.

15 DUVAL T. MCCUTCHENLNICHVOLASIS. RIZZO,

Examiners.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,202,674 August 24, 1965 Andre L. Langis et al.

It is hereby certified that error appears in the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below.

Column 2, lines 35 to 38, the formula should appear as shown belowinstead of as in the patent:

column 4, line 15, for "Calculated for C gH N O.HCl: C, 68.8%; H,7.58%;" read Calculated for C H N .I-ICl: N, 8.90; Cl,

11.28. Found: N, 8.63; Cl, 10.68. line 16, strike out "phenylacetamideas a colorless oily residue."; column 6, lines 43 and 44, for"hydrocarbon" read hydrogen column 10, line 12, -for "3.80 grams (1.0mode)" read 38.0 grams (1.0 mole) line 34, for "C H N .2HCl:" read C H N.HCl:

--; column 13, line 13, for "C1, 10.778 0" read Cl, 10.78%

Signed and sealed this 26th day of April 1966.

(SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner ofPatents

